Student Research: Wan-Fen Li

, , 1993
Faculty Advisor: Lucio G. Costa

Development of a Mouse Model for Studying Paraoxonase


Abstract

Organophosphates are neurotoxic inseticides which have been used increasingly sincec organochlorines were prohibited. Organophophates are activated by the cytochrome P450 system to the respective oxygen analogs which are potent inhibitors of acetylcholinesterase. Some toxic oxons can be hydrolyzed in the plasma and tissues by an arylesterase termed paraoxonase. Activity of serum paraoxynase differs among animal speciies and a substrate-dependent polymorphism has been demonstrated in the human population. It has been suggested that there is a correlation between low serum paraoxynase activity and susceptibility to poisoning by organophosphates.

The goal of this project was to develop a mouse model for studing the role of paraoxonase in organphosphate toxicity. Purified rabbit paraoxonase was administered to mice via different routes to increase the mouse serum paraoxonase activity. To examine whether the level of paraoxonase activity would affect organophosphate toxicity, female BALB/c mice were treated with chlorpyrifos-oxon (CPO) or chlorpyrifos (CPS). The injection of paraoxonase was able to protect mice against cholinesterase inhibition caused by either the toxic metabolite (CPO) or the parent compound (CPS). Paraoxonase exerted a protective effect when administered before and after exposure to CPS. The mouse paraoxonase gene has also been investigated. Homologous regions of human and rabbit genes were used as primers to ampligy mouse cDNA by PCS (Polymerase Chain Reaction). A segment of mouse cDNA (150 bp) has been isolated and sequenced. The result shows that paraoxonase gene is conserved in human, rabbits, and mice.